T‐cell “induced‐self” MHC class I/peptide complexes may enable “de novo” tolerance induction to neo‐antigens occurring outside of the thymus

Abstract

The hair follicle (HF) epithelium can present self-antigens to cognate CD8+ T cells. These cells express periodically during the hair cycle arising or age-related immunogenic proteins including HF-specific neo-antigens. We propose that IFNgamma derived from the respective antigen-specific T cells spotting the particular self-peptides may thereby significantly induce and alter self-antigen presentation ("induced-self").This induction, at first, may silence T cells, including neoepitope-specific T cells. As the thymus cannot significantly recapitulate neo-epitopes evolving in the periphery, we propose that peripheral tissue-specific induction of MHC molecules presenting exactly these neo-epitopes by self-MHC/ peptide-reactive CD8+ T cells is a key element of selftolerance. Subsequently, however, the local perpetuation and modification of the same crosstalk in the context of HF immune privilege collapse can invite HF immunopathology, as typically seen in alopecia areata. This concept may essentially complement thymus-based regulation models of self/nonself-discrimination beyond "missing-self" to the fine-tuned "induced-self" to ensure peripheral needs to maintain selftolerance in the case of "danger" and any "alteration of self".

Hair follicle immune privilege and its collapse in alopecia areata

“…All this supports the concept that one of the key functions of IP is to shield intra‐follicularly expressed (auto‐)antigens generated during anagen from immune recognition, and to induce a state of peripheral tolerance against them whenever they may become exposed to the immune system 1,52 . Beyond immediate HF protection from immune attack, HF IP might even promote peripheral self‐tolerance 52 . For example, mouse skin with all HFs in mid‐late anagen exhibits a profoundly immunoinhibitory milieu, 53,54 most likely due to the secretion of immunoinhibitory IP guardians by HFs.…”

“…While it is as yet unclear what exactly these HLA associations mean for the functionality of HF IP, it is reasonable to assume that the corresponding variations in MHC structure significantly influence the strength at which (auto‐)antigens are presented by HF keratinocytes via MHC class I to autoreactive CD8 + T cells, or by HF‐associated APCs via MHC class II molecules to autoreactive CD4 + T cells, that have escaped (HF‐dependent?) peripheral tolerance induction 52 . Subtle, genetically coded changes in MHC structure and function could thus greatly increase the risk of an anti‐HF autoimmune attack in the event of HF IP collapse (see below).…”

Human αβ and γδ T Cells in Skin Immunity and Disease

“…While the epithelial bulb of a normal anagen hair follicle does not express MHC Class I or MHC Class II; patients with alopecia areata exhibit increased MHC expression and adhesion molecule upregulation ( 130 , 131 ). Elevated numbers of Th1 cells in the skin of alopecia patients produce IFN-γ which induces the expression of MHC class I molecules and triggers perifollicular CD8 + T cell infiltration ( 101 , 132 , 133 ). The severity of alopecia areata is closely related to CD8 + T cell gene expression, with a positive correlation between CD8 + T cell-specific genes and alopecia areata severity ( 101 ).…”

Does Complement Have a Role in the Pathogenesis of Alopecia Areata?

“…Further research into self-antigens and “induced-self” has elucidated that hair follicles present self-antigens to CD8+ T cells at multiple stages of the hair cycle creating multiple CD8+ clones primed against hair follicle-specific neoantigens/epitopes. If the immune privilege of the hair follicle is disturbed, AA may occur [22]. …”